We found a striking, robust life-span extension effect of social interaction in Drosophila Sod mutants defective in Cu/Zn superoxide dismutase (SOD). Lacking SOD enzymatic activity hampers the ability of animals to clear the harmful reactive oxygen species (ROS) generated in aerobic metabolic process, leading to accelerated aging and excessive stress responses, and is implicated in several neurodegenerative diseases. We found that upon co-housing with younger or more active flies, Sod mutants display not only a doubled lifespan, but also improved stress-resistance and motor coordination. These phenotypes provide a sensitized system for intervention and for unraveling the interacting genetic networks and metabolic pathways underlying certain neuroprotective mechanisms and lifespan determination. We will adopt a multi-disciplinary approach with the molecular, genetic, physiological and behavioral tools developed in our lab and collaborators to facilitate correlation within the same individual or groups of flies subjected to studies at different levels. Aim1: To refine the behavioral experiments to reveal the nature of beneficial behavioral interactions for further understanding of the neuroprotective effect of social interaction in Sod flies. We aim to use the automated video tracking system, IowaFLI Tracker, newly developed in our lab in conjunction with other standard behavioral techniques. Aim2: Sod flies with or without co-housed helpers will be examined for key redox enzymes or their substrates by qRT-PCR and Western Blot analysis to uncover their potential roles in the helper effect, as suggested by their compensatory adjustments in ROS metabolism in this neuroprotective process. In addition a large extant collection of double mutants among genes controlling membrane excitability and metabolic pathways will facilitate construction of an interaction map linking metabolic pathways and neuronal excitability control emanating from Sod function. Missing links and new branches from prominent responder genes may emerge through a microarray analysis. Aim3: The beneficial effects of improved motor coordination and stress resistance will be further correlated with physiological modifications in neurons and neural circuits during aging of Sod flies co-housed with helpers. We will identify resilient physiological parameters as well as labile properties that are prone to Sod mutational perturbations. This will define in concrete physiological terms the landmarks of nervous system aging that are responsive to neuroprotective effect of social interactions.